Dataset Information

E22G Pathogenic Mutation of ?-Amyloid (A?) Enhances Misfolding of A?40 by Unexpected Prion-like Cross Talk between A?42 and A?40.

ABSTRACT: Cross-seeding of misfolded amyloid proteins is postulated to induce cross-species infection of prion diseases. In sporadic Alzheimer's disease (AD), misfolding of 42-residue ?-amyloid (A?) is widely considered to trigger amyloid plaque deposition. Despite increasing evidence that misfolded A? mimics prions, interactions of misfolded 42-residue A?42 with more abundant 40-residue A?40 in AD are elusive. This study presents in vitro evidence that a heterozygous E22G pathogenic ("Arctic") mutation of A?40 can enhance misfolding of A? via cross-seeding from wild-type (WT) A?42 fibril. Thioflavin T (ThT) fluorescence analysis suggested that misfolding of E22G A?40 was enhanced by adding 5% (w/w) WT A?42 fibril as "seed", whereas WT A?40 was unaffected by A?42 fibril seed. 13C SSNMR analysis revealed that such cross-seeding prompted formation of E22G A?40 fibril that structurally mimics the seed A?42 fibril, suggesting unexpected cross talk of A? isoforms that potentially promotes early onset of AD. The SSNMR approach is likely applicable to elucidate structural details of heterogeneous amyloid fibrils produced in cross-seeding for amyloids linked to neurodegenerative diseases.

SUBMITTER: Yoo BK

PROVIDER: S-EPMC6408951 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Publications

E22G Pathogenic Mutation of β-Amyloid (Aβ) Enhances Misfolding of Aβ40 by Unexpected Prion-like Cross Talk between Aβ42 and Aβ40.

Yoo Brian K BK Xiao Yiling Y McElheny Dan D Ishii Yoshitaka Y

Journal of the American Chemical Society 20180220 8

Cross-seeding of misfolded amyloid proteins is postulated to induce cross-species infection of prion diseases. In sporadic Alzheimer's disease (AD), misfolding of 42-residue β-amyloid (Aβ) is widely considered to trigger amyloid plaque deposition. Despite increasing evidence that misfolded Aβ mimics prions, interactions of misfolded 42-residue Aβ42 with more abundant 40-residue Aβ40 in AD are elusive. This study presents in vitro evidence that a heterozygous E22G pathogenic ("Arctic") mutation o ...[more]

PMID: 29425039

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Project description:BackgroundCathepsin D (CatD) is a lysosomal protease that degrades both the amyloid β-protein (Aβ) and the microtubule-associated protein, tau, and has been genetically linked to late-onset Alzheimer disease (AD). Here, we sought to examine the consequences of genetic deletion of CatD on Aβ proteostasis in vivo and to more completely characterize the degradation of Aβ42 and Aβ40 by CatD.MethodsWe quantified Aβ degradation rates and levels of endogenous Aβ42 and Aβ40 in the brains of CatD-null (CatD-KO), heterozygous null (CatD-HET), and wild-type (WT) control mice. CatD-KO mice die by ~ 4 weeks of age, so tissues from younger mice, as well as embryonic neuronal cultures, were investigated. Enzymological assays and surface plasmon resonance were employed to quantify the kinetic parameters (KM, kcat) of CatD-mediated degradation of monomeric human Aβ42 vs. Aβ40, and the degradation of aggregated Aβ42 species was also characterized. Competitive inhibition assays were used to interrogate the relative inhibition of full-length human and mouse Aβ42 and Aβ40, as well as corresponding p3 fragments.ResultsGenetic deletion of CatD resulted in 3- to 4-fold increases in insoluble, endogenous cerebral Aβ42 and Aβ40, exceeding the increases produced by deletion of an insulin-degrading enzyme, neprilysin or both, together with readily detectable intralysosomal deposits of endogenous Aβ42-all by 3 weeks of age. Quite significantly, CatD-KO mice exhibited ~ 30% increases in Aβ42/40 ratios, comparable to those induced by presenilin mutations. Mechanistically, the perturbed Aβ42/40 ratios were attributable to pronounced differences in the kinetics of degradation of Aβ42 vis-à-vis Aβ40. Specifically, Aβ42 shows a low-nanomolar affinity for CatD, along with an exceptionally slow turnover rate that, together, renders Aβ42 a highly potent competitive inhibitor of CatD. Notably, the marked differences in the processing of Aβ42 vs. Aβ40 also extend to p3 fragments ending at positions 42 vs. 40.ConclusionsOur findings identify CatD as the principal intracellular Aβ-degrading protease identified to date, one that regulates Aβ42/40 ratios via differential degradation of Aβ42 vs. Aβ40. The finding that Aβ42 is a potent competitive inhibitor of CatD suggests a possible mechanistic link between elevations in Aβ42 and downstream pathological sequelae in AD.

Dataset Information

E22G Pathogenic Mutation of ?-Amyloid (A?) Enhances Misfolding of A?40 by Unexpected Prion-like Cross Talk between A?42 and A?40.

Publications

E22G Pathogenic Mutation of β-Amyloid (Aβ) Enhances Misfolding of Aβ40 by Unexpected Prion-like Cross Talk between Aβ42 and Aβ40.

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